Studies in the first period of these projects have demonstrated that the measurement of free erythrocyte protoporphyrin is an exquisite indicator of Pb poisoning. Free erythrocyte porphyrins can be measured rapidly and precisely by a micromethod (FEP test). The proposed research will investigate the clinical significance of hemotological evidence of lead toxicity in asymptomatic children with moderately elevated body burden of lead. These studies will investigate whether, at equal blood Pb levels, more pronounced metabolic effects reflect a greater body burden of lead and greater evidence of neurological toxicity. These studies will evaluate the different content and the molecular species of protoporphyrin present in red cells fractionated according to age to provide an insight into the temporal sequence of lead exposure at time of testing to be used in diagnosis and treatment. These studies will also evaluate the effect of Fe deficiency on porphyrin elevation. An epidemiological study will be performed in children, as well as in adults, to substantiate the evidence for a dose-effect relationship between body burden of Pb and metabolic interference. These studies will be performed in individuals with blood Pb in the range presently considered "normal," to demonstrate evidence of metabolic effects even in this range. These studies will investigate the lag phase between exposure of animals to lead and elevation of porphyrins as well as the sequence of production of free and Zn-chelated protoporphyrin. These studies will evaluate the mechanism of action of lead on the mitochondrial enzyme ferrochelatase and evaluate whether this is a specific effect or an interference with mitochondrial function and Fe transport.